Reviews and Overviews

Toward Reformulating the Diagnosis of Schizophrenia

Ming T. Tsuang, M.D., Ph.D.,
D.Sc., F.R.C.Psych.
William S. Stone, Ph.D.
Stephen V. Faraone, Ph.D.
REFORMULATING SCHIZOPHRENIA
TSUANG, STONE, AND FARAONE

Objective: The authors assess implications of DSM criteria for schizophrenia by

reviewing the criterias 1) emphasis on psychotic features, 2) dissociation of symptoms from their etiology, 3) exclusive reliance on clinical features but exclusion of
biological indicators, and 4) classification
of schizophrenia as a discrete category.
The authors then discuss alternative conceptions of schizophrenia that take into account recent data concerning its genetic
and neurodevelopmental origins and its
pathophysiological substrates.
Method: The historical development of
diagnostic criteria for schizophrenia is reviewed in the context of recent published
data on the biology and development of
schizophrenia.
Results: Growing evidence suggests that
symptoms of psychosis may be a common
end-state in a variety of disorders, includ-

ing schizophrenia, rather than a reflection

of the specific etiology of schizophrenia.
Features occurring before the advent of
psychosis that are clinical, biological, and/
or neuropsychological in nature may constitute evidence of a genetic predisposition
toward schizophrenia (schizotaxia) and
may provide more specific information
about the genetic, pathophysiological, and
developmental origins of schizophrenia.
Conclusions: The success of efforts to
treat and prevent schizophrenia will depend to an important extent on an accurate understanding of its causes. This goal
can be furthered by conducting field trials
to develop research criteria to assess the
value of a developmentally sensitive, biologically informed approach to classification that would consider schizotaxia with
psychosis (schizophrenia) and schizotaxia
alone as distinct diagnostic conditions.
(Am J Psychiatry 2000; 157:10411050)

chizophrenia has long been recognized as a devastating disorder for patients and their families. Although substantial progress has been achieved both in diagnosis and
treatment of the disorder and in understanding the disorders neurobiological substrates, a full understanding of its
origins and pathogenic mechanisms remains elusive. One
obstacle to better understanding the causes of schizophrenia may be the current conceptualization of the disorder, as represented by its diagnostic criteria. Despite
progress in moving toward the implementation of a scientific psychiatric nosology, the conceptualization of schizophrenia is an issue not easily amenable to empirical resolution (1). DSM-IV and other nosologies provide a
foundation for clinical diagnosis, but as various researchers have pointed out (e.g., references 2, 3), there is little basis for regarding DSMs operational definition as the true
construct of schizophrenia.
This paper considers ways to reformulate the diagnostic
criteria for schizophrenia to promote a fuller understanding of the disorders etiology. The development of diagnostic criteria for schizophrenia in DSM are considered first,
with special attention to their emphasis on psychosis. The
case for initiating field trials to determine whether biological or neuropsychological criteria should be incorporated
into a reformulated research diagnosis is then considered.
Throughout the paper, the term psychosis is used to enAm J Psychiatry 157:7, July 2000

compass hallucinations, delusions, and/or gross disorganization of thought or behavior.

Diagnostic Criteria for Schizophrenia:

Historical Background
Toward the end of the nineteenth century, Kraepelin differentiated dementia praecox and manic-depressive psychoses (4). Dementia praecox described patients who
showed a global disruption of perceptual and cognitive
processes (dementia) and an early onset (praecox). Kraepelins dementia praecox patients usually had an illness
onset in early adulthood and a progressively deteriorating
course with no return to premorbid levels of function.
These features contrasted with the relatively intact thinking, later onset, and episodic nature of illness in patients
with manic-depressive psychoses, whose episodes of psychopathology alternated with periods of normal function.
Bleuler used Kraepelins systematic classification of psychoses and a theoretical model of etiological processes to
reformulate dementia praecox as schizophrenia, from the
Greek words for splitting of the mind (5). He described
four fundamental symptoms: ambivalence, disturbance of
association, disturbance of affect, and a preference for
fantasy over reality. To Bleuler, these symptoms reflected
schizophrenias fundamental defect: the separation or
splitting of the normally integrated functions that coordi-

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nate thought, affect, and behavior. It is noteworthy that

two psychotic features emphasized by todays DSMhallucinations and delusionswere not crucial for Bleulers
diagnosis of schizophrenia.
Bleulers emphasis on theory as a means for determining the diagnostic relevance of signs and symptoms contrasted sharply with Kraepelins reliance on empirical observations. Bleulers approach was also notable for three
other reasons. First, his reformulation of dementia praecox as the group of schizophrenias foreshadowed the
contemporary view that schizophrenia is a heterogeneous
group of disorders with similar clinical presentations. Second, Bleuler included defects in affect as a core feature of
the disorder. Third, his view of schizophrenia allowed for
the possibility of recovery.
Kraepelins and Bleulers observations evolved into todays psychiatric classification systems: the ICD and the
APAs DSM. In addition to its use of Kraepelins and
Bleulers views on the signs and symptoms of schizophrenia, the first DSM defined schizophrenia in a way that at
least implied environmental causes. For example, all
schizophrenic (and other psychiatric) diagnoses included
the term reaction (as in schizophrenic reaction, simple
type). Moreover, definitions were vague, did not include
specific operational criteria, and did not discuss differential diagnoses. Such imprecise definitions allowed clinicians much discretion in making diagnoses. As a result, in
the United States, schizophrenia became the diagnosis of
choice for psychotic conditions that lacked a clear organic etiology. DSM-II dropped the term reaction from
its diagnoses and added some discussion of differential diagnoses, but continued the DSM-I tradition of brief, vague
descriptions of schizophrenic disorders, without specific
operational criteria. Interestingly, both of these early systems viewed psychosis as the key feature of the disorder.
DSM-II did contain a category (schizophrenia, latent
type) to describe people with clear symptoms of schizophrenia but no history of a psychotic schizophrenic
episode. This category was intended to encompass individuals with a variety of conditions (e.g., incipient,
prepsychotic, and borderline schizophrenia, as well as
schizophrenic reaction, chronic undifferentiated type,
from DSM-I). The presence of this category did not detract
from the primacy of psychotic symptomsthe term latent implied the presence of an underlying or as yet unexpressed psychosis (because psychotic symptoms were absent). It did, however, reflect an important attempt to
clarify the role of psychosis in schizophrenic illness.
DSM-III brought about a sea change in psychiatric classification, spearheaded by the neo-Kraepelinian movement in the 1960s and 1970s (e.g., references 6, 7) and by
investigators in psychiatry and clinical psychology who
emphasized the importance of empirical, psychometric
validation of psychiatric syndromes (e.g., reference 8).
DSM-III contained several innovations, including field
tests of diagnostic reliability, specific inclusion and exclu-

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sion criteria for diagnoses, multiaxial diagnosis, and a focus on the description of syndromes and course of disorders rather than inferences about their etiology. This latter
point made psychiatric diagnosis more explicitly consistent with the diagnosis of other medical disorders of unknown etiology (2, 6).
DSM-IIIs use of clearly defined criteria limited clinicians discretion and narrowed the construct of schizophrenia. This development improved the clinical homogeneity of the disorder, better delimited it from other serious
mental illnesses, and raised diagnostic reliability to respectable levels. Nevertheless, DSM-III retained the view
that psychosis was fundamental to the definition of
schizophrenia. The primacy of psychosis in defining
schizophrenia also survived DSM-IIIs revision and its
evolution into DSM-IV. Psychosis was de-emphasized in
DSM-IV, in that a patient could receive a diagnosis of
schizophrenia according to DSM-IV criteria without having delusions or hallucinations. In that case, however,
gross disorganization of speech and/or behavior, which
are also psychotic symptoms, would still be required because criterion A (i.e., characteristic symptoms) requires
at least two of the five symptoms in the category. Thus,
four of the five symptoms are still related to psychosis
(negative symptoms are the fifth symptom in the category). Moreover, delusions alone can satisfy the criterion if
they are bizarre, and hallucinations alone can satisfy the
criterion if they involve one or more voices engaging in
running commentary or ongoing conversation. (The diagnostic importance of these latter symptoms reflects
particularly the influence of Schneiderian concepts, discussed below). Diagnostic changes in DSM-IV thus expanded the nature of the required psychotic symptoms
more than they de-emphasized psychosis itself.
The importance of psychotic symptoms in diagnosis extends to other diagnostic systems. Schneiders first-rank
symptoms (9), which form the basis of nuclear schizophrenia, are types of hallucinations and delusions that
have come (more than other, second-rank symptoms) to
characterize the nature of psychosis in the disorder. More
important, they have helped to define the disorder itself,
although Schneider himself viewed them more as diagnostic tools than as theoretical constructs about the etiology of the disorder (10). First-rank symptoms heavily influenced the development of Research Diagnostic Criteria
for schizophrenia, which in turn formed the basis of DSMIII criteria for schizophrenia. These criteria particularly
continue to influence ICD-10 in the first three symptoms
groups that have special importance for the diagnosis of
schizophrenia.

Limitations of Current Criteria

for Schizophrenia
Stringent, narrow diagnostic criteria for disorders such
as schizophrenia were needed in the 1970s and 1980s to
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TSUANG, STONE, AND FARAONE

improve the reliability of clinical diagnoses. They were

also needed to counteract the prevailing view that mental
illnesses were myths that harmed patients by stigmatizing them with damaging diagnostic labels. Periodic revisions of the major classificatory systems have continued
to refine diagnoses, increase their reliability, and facilitate
the adoption of empirical methods to determine which
symptoms most appropriately characterized specific disorders. Consequently, communications about, and diagnoses of, mental disorders are far more standardized
among mental health professionals and other interested
parties (e.g., HMOs, insurance companies, educational institutions) than they used to be, and the rationales for specific diagnostic criteria are much clearer. The reliability of
diagnoses provided by recent DSMs has also benefited research to the extent that the clinical characteristics of
samples are more standardized across studies and are
thus more easily replicated. Moreover, the use of stringent
diagnostic criteria laid the groundwork for studies to assess the validity of the concept of schizophrenia, and these
studies have in fact demonstrated substantial diagnostic
validity. Schizophrenia can be distinguished from other
disorders; for example, it shows familial loading and
greater levels of functional impairment that may predict
larger numbers of recurrent episodes.
Despite the many advances of DSM-III and its successors, further improvement in the classification of schizophrenia is possible. One way to proceed is to consider the
cup half full rather than half empty and to fill it further by
integrating current knowledge with existing conceptual
and classificatory schemes. In this context, at least three
limitations of the current diagnostic criteria can be addressed: 1) their view of schizophrenia as a discrete category, 2) their emphasis on psychosis, and 3) their use of descriptive attributes and neglect of information about the
etiology and pathophysiology of the disorder. Each of these
limitations leads to the same question: Can the reliability
of the DSM-IV diagnosis of schizophrenia be retained
while the validity of diagnosis is increased? These points
are addressed in more detail in the following sections.

DSM-IV Schizophrenia
Is a Discrete Category
DSM-IV defines schizophrenia, like other disorders, as a
discrete category, not a quantitative dimension. Curiously,
DSM-IV also states there is no assumption that each category of mental disorder is a completely discrete entity
with absolute boundaries dividing it from other mental
disorders or from no mental disorder (p. xxii). Despite
this qualification, the DSM-IV classification of schizophrenia presents the disorder as a discrete condition.
One implication of this approach, however implicit, is
that schizophrenia differs qualitatively from states of
health or normalcy. According to this approach, schizophrenia begins with the onset of the symptoms listed in
Am J Psychiatry 157:7, July 2000

DSM-IV. Before that time, the disorder cannot be validly

recognized. If an individual does not have the symptoms of
schizophrenia listed in DSM-IV and does not meet the criteria for some other disorder, then no psychiatric diagnosis
may be given, although neither clinicians nor researchers
would assume necessarily that the individual was normal.
However, the failure to meet diagnostic criteria remains
potentially consequential. Clinically, it can influence what
type of treatment or services a patient receives. From a research perspective, it can determine whether an individual
is accepted into a study of schizophrenia or how he or she
is classified in a genetic investigation.
In addition, the use of discrete categories raises potential problems for cases in which the symptoms of multiple
disorders are present, as it may result in artificial boundaries between conditions and elevated rates of comorbidity (11). Certainly, dimensional models of psychopathology have conceptual and pragmatic limitations as well
(1113). For example, although a variety of studies have
identified dimensions that may underlie diagnostic criteria for schizophrenia (e.g., positive, negative, and disorganized symptoms), there are still questions about which dimensions, and how many, should be emphasized (e.g.,
references 1417). But the debate about the dimensionality of schizophrenic psychopathology avoids the main
question: does a dimensional model more accurately describe the biological nature of schizophrenia? Is it more
valid?
A dimensional view of schizophrenia is especially consistent with multigene models of inheritance, and these
models provide the best account of the familial transmission of schizophrenia (18, 19). Multigene models assume
that multiple genes combine with one another and with
environmental factors to cause schizophrenia. Because
multiple genes and environmental risk factors are involved, it is possible for people to have low, moderate, or
high doses of the risk factors that predispose to schizophrenia. People with very high doses are at high risk for
schizophrenia, and those with moderate doses may have
related conditions such as schizotypal personality disorder, negative symptoms, neuropsychological impairment,
or other neurobiologic manifestations of the predisposition to schizophrenia (20).
In fact, a partial foundation for a dimensional view of
the biological/clinical manifestations of the vulnerability
to schizophrenia already exists in the body of research
about schizotaxia, a term originally introduced by Meehl
(21) to describe the unexpressed genetic predisposition to
schizophrenia. Meehl suggested that individuals with
schizotaxia would develop either schizotypy or schizophrenia, depending on the protection or liability afforded
by environmental circumstances. But, in a subsequent revision, he proposed that schizotaxia need not progress
into either of these more overt conditions (22). Given current data showing that, in addition to genes, environmental events (e.g., obstetric complications, viruses) augment

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susceptibility to schizophrenia, Faraone et al. (23) proposed using the term schizotaxia to indicate the premorbid neurological substrate of schizophrenia. The addition
of environmental events to genetic liabilities differs from
Meehls view of schizotaxia, which focused on only the biological consequences of genes. The addition was made
because both types of events may occur early in development, interact with each other, and produce neurobiological liabilities for schizophrenia.
More than three decades after the idea of schizotaxia was
introduced, a body of research has developed suggesting
that it may be a clinically consequential condition. In fact,
studies of the nonschizotypal and nonpsychotic relatives
of patients with schizophrenia have shown that schizotaxia
is not merely a theoretical construct but an actual condition with distinctive psychiatric and neurobiological features. These features include negative symptoms, neuropsychological impairment, deviant eye tracking, and
structural brain abnormalities (23). Thus schizotaxia represents both a clinically meaningful condition in its own
right and a risk factor for subsequent psychosis.
Schizotaxia is a much broader construct than schizophrenia. Empirical studies suggest that the basic symptoms of schizotaxia may occur in 20% to 50% of first-degree relatives of patients with schizophrenia (20, 24). In
comparison, only about 10% of relatives will become psychotic, and less than 10% will develop schizotypal personality disorder (25, 26). These figures suggest that schizotaxia does not lead inevitably to schizotypal personality
disorder or to schizophrenia. The view of schizotaxia as a
relatively stable condition that does not lead to a more serious disorder in most individuals contrasts somewhat
with Meehls view that it will progress in most people.

Psychosis and the Definition

of Schizophrenia
In the DSMs, psychosis has been the sine qua non for
schizophrenia (as noted earlier, psychotic symptoms include delusions, hallucinations, and gross disorganization
of behavior or thought). But is the level of importance afforded to psychosis appropriate for what research and
clinical experience show to be a nonspecific indicator of
severe mental illness? An alternative perspective is provided by Crows theory describing a continuum of psychosis that crosses diagnostic boundaries (15, 2729). Crow
suggested that schizophrenia, schizoaffective disorder,
and affective illness exist along one or more such continua. Although he accepted the concept of prototypical
entities corresponding to schizophrenia and affective illness, he rejected the idea that they had distinct etiologies.
Rather, he suggested that individual disease entities did
not actually exist; instead, natural variation along one or
more dimensions produced the prototypical disorders. He
postulated that a common genetic deficit, located in the
pseudoautosomal region of the sex chromosomes, was

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shared by psychotic disorders, and he hypothesized that

genes related to psychosis were responsible for cerebral
dominance and the localization of language.
Support for the pseudoautosomal hypothesis is weak
(3032), and a psychosis gene shared by all psychotic disorders has yet to be discovered. Nevertheless, Crows view
of psychosis is intriguing. If, in fact, psychosis has an etiology apart from other core symptoms of schizophrenia,
then DSMs diagnostic focus on psychosis in schizophrenia could be a mistake. In the hunt for the causes of
schizophrenia, psychosis could be a red herring.
A variety of evidence sustains this view. It is clear that
psychosis is not specific to schizophrenia or even to psychiatric disorders. It occurs in neurological disease (e.g.,
Alzheimers disease, Huntingtons disease, schizophrenialike psychosis of epilepsy, vascular dementia, and traumatic brain injury), and it can be caused by a range of toxic
substances. Beyond the prima facie evidence that similar
appearing psychoses occur in diverse conditions, Schneiderian first-rank symptoms appear commonly in psychotic conditions other than schizophrenia (33). Moreover, in studies that have used factor analysis, measures of
psychosis did not differentiate schizophrenia from other
forms of psychopathology (16, 34).
For example, Bell et al. (14) showed that duration of illness and exclusion of affective symptoms correctly classified 97% of first-episode psychosis patients as having
DSM-III-R schizophrenia and also correctly identified 97%
of such patients who did not have schizophrenia. The inclusion of DSM-III-Rs psychosis criterion (criterion A)
was not necessary and did not improve the prediction.
Serretti et al. (35) obtained a four-factor solution for items
on the Operational Criteria Checklist for Psychotic Illness
in a large group of inpatients with either DSM-III-R
schizophrenia or a DSM-III-R mood disorder. Although
they found that two of the factors were more closely related to affective disorders and two were more closely related to schizophrenia, the psychopathology of subjects
with schizophrenia overlapped that of patients with bipolar disorder on a disorganization factor. The presence of
psychotic symptoms among other diagnostic groups has
also been described (15, 36), although the issue remains
controversial (e.g., reference 37).
Notably, several molecular genetic studies have failed to
find linkage to schizophrenia on the basis of the DSM diagnosis but instead found stronger evidence for linkage
when other psychotic disorders were included in the phenotype. For example, Maziade et al. (38) failed to detect
linkage at 6p24-22 in 18 large multigenerational pedigrees
from Eastern Quebec, using either broad or narrow definitions of schizophrenia. However, they did find suggestive
evidence in one large pedigree that the locus was associated with vulnerability to both schizophrenia and bipolar
disorder when they utilized a broad phenotypic definition
that included schizophrenia, schizoaffective disorder,
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schizophreniform disorder, bipolar disorder (I and II), and

major depression (recurrent).
Moreover, other researchers have suggested that at least
one disorder in the schizophrenia spectrumschizoaffective disordermight belong to an affective disorder spectrum as well (39). Consistent with this possibility, evidence
for linkage has been obtained at this locus (on chromosome 6) for bipolar disorder in Old Order Amish pedigrees
(40). Similarly, the chromosome 10p region was implicated for both schizophrenia and bipolar disorder in the
NIMH Genetics Initiative pedigrees (4143).
Wildenauer et al. (44) reported suggestive evidence of
linkage to a region on chromosome 18p, by using a sibpair analysis. Their findings are interesting, partly because
they obtained their highest lod scores when they used a
broad phenotypic definition that included schizophrenia
patients relatives with bipolar disorder and major depression, in addition to relatives with schizophrenia and
schizoaffective disorder. This group recently reported a
lod score of 3.1 using this approach and confirmed in principle findings reported by Maziade et al. (38) at chromosome 6p24-22. Moreover, the chromosome region at 18p
has also been implicated in bipolar disorder (45, 46).
One explanation for the similarities between psychotic
symptoms in different disorders may be the neurotoxic
effects of psychosis itself. Several lines of evidence are
consistent with this possibility. One stems from observations that clinical outcomes of schizophrenia improve
when treatment is obtained early in the illness (47). A
growing body of evidence has shown that some patients
with schizophrenia show neurobiological abnormalities
suggestive of a degenerative process, such as enlarged
ventricles, loss of tissue volume, degeneration of membrane phospholipids, and/or delayed P300 waves in
event-related potential paradigms (48).
This discussion provides support for the view that at
least some aspects of psychosis share common elements
across disorders, both etiologically and perhaps in their
pathophysiological effects as well. It is consistent with
Crows notion of a continuum of psychoses, in regard to
their common phenomenology and etiology. It differs
from Crows view, however, in its implications for the construct of schizophrenia. Similarities between psychotic
states do not necessarily imply that the underlying disorders lie on the same continuum. An alternative formulation is that psychotic states may impair functioning in a
relatively global manner and may have toxic effects of
their own. Thus their net effect may be to emphasize superficial similarities between psychotic disorders, while
obscuring more subtle but defining differences between
them.
In summary, at least two problems with the DSMs use of
psychosis as a sine qua non for schizophrenia may be
identified. Mounting evidence suggests that psychosis is
the fever of severe mental illnessa serious but nonspecific indicator. Moreover, psychosis is an end-state condiAm J Psychiatry 157:7, July 2000

tion that, in comparison with other indicators, is more distal from schizophrenias causes and pathophysiology.
Because, as we discuss next, more proximal indicators exist, the focus on psychosis may hinder progress in searching for the causes of schizophrenia. This view is consistent
with that advanced recently by Andreasen (49), who proposed that clinical symptoms were too variable to define
the schizophrenia phenotype and argued instead that the
phenotype should be defined by a more fundamental disruption in mental processes occurring as a consequence
of a disruption in neural circuitry (p. 782).

Separation of Diagnostic Criteria

and Concepts of Etiology
A key innovation of DSM-III was its explicit separation
of diagnostic criteria from speculation about etiology. At
the time DSM-III was developed, this separation was essential because theories of etiology had not yet been subjected to empirical tests. But has DSM-IV, by holding fast
to this approach, limited its ability to create more valid
diagnoses?
What, for example, would Kraepelin think about the
current criteria for schizophrenia? Perhaps he would be
pleased that, on the threshold of the twenty-first century,
so many of his views have been retained by contemporary
nosologists. Or perhaps he might be puzzled that contemporary psychiatrists, unlike their colleagues in other medical fields, are still using signs and symptoms that had
been discovered in the nineteenth century.
The point here is simple. DSMs rejection of theoretical
speculation about etiology should not lead to the rejection
of empirical facts about etiology as being relevant to diagnosis. The puzzle of schizophrenia has not yet been
solved, although many pieces of the puzzle are falling into
place. Perhaps this empirically validated knowledge about
the disorder should be incorporated into diagnostic criteria. If it is not, there exists a significant risk of maintaining
a stagnant nomenclature that will not provide a solid
foundation for further research.
There is also a risk of a continuing disconnection of
treatment from etiology. Since the introduction of antipsychotic medications, pharmacologic treatments have focused on alleviating the most acute, florid symptoms of
schizophreniai.e., those related to psychosis. Although
several newer antipsychotic medications also alleviate selected negative symptoms and cognitive deficits, treatment remains symptomatic. It is not aimed at correcting
specific causes of the disorder, nor is it aimed at preventing its onset.
Presumably, knowledge about the etiology of schizophrenia would facilitate the development of more targeted
treatment strategies and, possibly, the use of safer treatments. For example, if the causes of schizophrenia were
known, there would be no a priori reason why treatments
to prevent it would necessarily involve antipsychotic med-

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REFORMULATING SCHIZOPHRENIA

ications. Of course, research on prevention strategies is

difficult at the present time, partly because the etiology remains unclear but also because the DSM-IV definition of
schizophrenia requires the presence of psychotic symptoms. Consequently, the administration of antipsychotic
medications to nonpsychotic individuals with no schizophrenia-related diagnoses is difficult to justify.
An analogy with late-life dementing disorders may be
instructive. If vascular dementias and Alzheimers disease
were assessed only when clinical and cognitive deficits
had progressed to levels that are moderately severe or
greater, then the clinical presentations would look quite
similar. Moreover, most treatments would be aimed at reducing the most florid symptoms (e.g., psychosis, agitation, disorganization). On the other hand, if the diagnosis
is made when the symptoms are milder, the patterns of
impairment will likely differ from each other in ways that
better reflect their unique etiologies. If the developmental
trajectories of the disorders are also considered, then, at
least in the case of vascular dementia, risk factors such as
hypertension might be controlled to prevent or modify the
course of the disorder itself.
It is certainly counterintuitive to think of psychosis as an
end state of schizophrenia. However, there is evidence suggesting that the pathophysiology of schizophrenia is in
place long before the first psychotic episode. For example,
several researchers have sketched neurodevelopmental
models of schizophrenia proposing that some combination of genes and environmental events leads to maldevelopment of the brain as early as the second trimester of life
(5053). This maldevelopment creates a neurodevelopmental syndrome that, as studies of relatives of patients
with schizophrenia have shown, can be characterized by
neuropsychological, psychophysiological, and neuroimaging measures (23). For reasons that are still unknown, this
syndrome sometimes expresses psychosis, and sometimes
it does not. Notably, these indicators of the syndrome are
more proximal to schizophrenias initial causes than is psychosis. Could they be useful as diagnostic criteria?
Evidence for a neurodevelopmental theory of schizophrenia comes from several sources. Among these, first,
are studies showing higher than expected frequencies of
obstetrical complications and prenatal exposure to viruses in individuals who later develop schizophrenia (54).
Second, postmortem studies of patients with schizophrenia have shown brain abnormalities indicative of developmental problems in the second or third trimester of pregnancy, such as altered cell migration in the hippocampus,
cingulate gyrus, and prefrontal cortex (55). Also, some
subjects with schizophrenia show a cavum septum pellucidum (a failure to fuse two laminar membranes), an event
that usually occurs in the second or third trimester (56).
Third, evidence from a rodent model of perinatal damage
(an excitotoxic lesion) to the ventral hippocampus is also
consistent with the neurodevelopmental theory. In this
model, the rats appear normal until puberty (despite the

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hippocampal damage) but then develop hyperdopaminergic behaviors (57, 58).

Fourth, there is considerable evidence of neuropsychological deficits, especially in attention, long-term verbal
memory, and executive functions (e.g., planning, organizing problem solving, and abstracting) in nonpsychotic,
first-degree relatives of patients with schizophrenia (e.g.,
references 23, 59, 60). Fifth, negative symptoms are frequent among nonpsychotic, first-degree relatives of people with schizophrenia. For example, Tsuang et al. (61)
noted that negative symptoms (especially flat affect and
avolition), but not positive symptoms, were significantly
elevated in schizophrenia families. Odd speech, social
dysfunction, and negative symptoms strongly discriminated relatives of patients with schizophrenia from control subjects in the Roscommon family study (62). In
contrast, positive symptoms, suspicious behavior, and
avoidant symptoms were less discriminating.
Sixth, there is evidence that the neurodevelopmental
disorder may be progressive. For example, several studies
have provided evidence that enlarged ventricles and decreased tissue volumes were not necessarily related to
psychosis (63). In one of these studies, first-episode patients with schizophrenia showed ventricular enlargement and decreased cortical volume, but their intracranial
volume did not differ from that of the control group (64).
Because intracranial volume is constant after brain growth
reaches maximal levels at around 5 years of age (the skull
sutures fuse), it is likely that the tissue loss occurred after
the pre- and perinatal periods but before the onset of psychotic features. Cannon et al. (65) reported that the nonpsychotic offspring of one or two parents with schizophrenia were more likely than comparison subjects to show
sulcal enlargement. Those with two affected parents
showed more enlargement than did those with one affected parent. Although ventricular enlargement was also
associated with a history of obstetric complications, sulcal
enlargement was not. The same group of researchers reported that schizotypal and schizophrenic groups both
showed larger ventricles and sulci than comparison subjects (66). The extent of sulcal enlargement did not differ
between the (nonpsychotic) schizotypal and schizophrenic groups, but ventricular enlargement was greater
in the schizophrenic group.
These studies support the idea that schizophrenic disease begins before the onset of psychosis and expresses itself biologically in characteristic ways. One way to integrate these findings is to conceptualize these factors (e.g.,
biological abnormalities, biological relatedness to a family
member with schizophrenia, selected neuropsychological
deficits, and history of obstetric complications) as risk factors for schizophrenia that vary along dimensions of severity. As noted previously, they may also represent components of a clinical syndrome (schizotaxia) that may or
may not progress to psychosis. Because many biological or
neuropsychological abnormalities start before the onset
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of psychosis, but psychosis itself may be associated with

neurobiological substrates that are at least partly independent of those related to schizophrenia, studies of schizophrenia could confound antecedent effects of schizophrenia genes with consequent effects of psychosis. To the
extent that this confounding occurs, diagnostic criteria
that restrict the definition of schizophrenic illness to the
onset of psychosis may hinder neurobiological research
into its etiological bases.
The value of relatively specific neurobiologic indicators
has been demonstrated already in genetic studies. For example, Arolt et al. (67) used deficits in eye tracking as a
phenotype and obtained evidence of genetic linkage on
chromosome 6p. Freedman et al. (68) used deficits in P50
waves in sensory gating paradigms as a phenotype and
obtained evidence in favor of linkage at chromosome
15q13-14. Other abnormalities sensitive to schizophrenias neurodevelopmental originsi.e., schizotaxiainclude allusive thinking (69), neurologic signs (70), characteristic auditory evoked potentials (71), neuroimagingassessed brain abnormalities (72), and neuropsychological impairment (73).
The representative studies listed above provide abundant support for the validity of schizotaxia as a concept,
but they do not validate schizotaxia as a specific syndrome. To accomplish that goal, field trials will be needed
to determine which abnormalities have the requisite reliability, sensitivity, and specificity to warrant inclusion in
diagnostic criteria sets. It would be premature at this point
to attempt to develop clinical criteria for schizotaxia. Instead, the development of research criteria that could be
used to validate (or disprove) the syndrome poses the
more immediate challenge.

Reformulating the Diagnosis

of Schizophrenia
As the previous discussion suggests, two aspects of the
diagnostic criteria for schizophrenia should be reconsidered: their emphasis on psychosis and their reliance on
signs and symptoms that are distal to the disorders etiology and pathophysiology. Such an approach would be a
radical departure from tradition, and any changes in the
diagnosis will require a strong empirical foundation. The
lack of such a foundation has heretofore prevented the inclusion of measures of biological or neuropsychological
abnormalities in previous versions of the DSM.
As discussed above, the concept of schizotaxia is especially useful for this purpose. Schizotaxia is still an evolving concept, not a disorder with set criteria. Tsuang et al.
(74) recently operationalized research criteria for schizotaxia on the basis of a combination of negative symptoms
and neuropsychological deficits, two areas that have been
the focus of the most robust findings in first-degree relatives of patients with schizophrenia. To meet the criteria
for schizotaxia of Tsuang et al., subjects must show modAm J Psychiatry 157:7, July 2000

erate or higher levels of both negative symptoms and neuropsychological impairment. A moderate or higher level of
negative symptoms is defined as six scores of 3 or higher
on items of the Scale for the Assessment of Negative
Symptoms (75). Neuropsychological impairment is defined as two standard deviations below normal in one cognitive domain and at least one standard deviation below
normal in a second cognitive domain in tests of attention,
long-term verbal memory, and executive function (e.g.,
planning, organizing problem solving, and abstraction).
These criteria are tentative, and much research will be
needed for their refinement and validation. As a preliminary step in that direction, Tsuang et al. reported a treatment study of four adult, first-degree relatives of patients
with schizophrenia who met criteria for schizotaxia (74).
For inclusion, subjects had to 1) be first-degree relatives of
patients with schizophrenia, 2) speak English as a first language, 3) have an estimated IQ score of at least 70, 4) be
1950 years of age (the age range was partly related to administration of a treatment), and 5) provide informed consent to participate. Exclusion criteria were designed to
minimize the influence of comorbid neurological, psychiatric, or other medical conditions (e.g., head injuries, current substance abuse, or history of electroconvulsive
treatments) that could mimic symptoms of schizotaxia.
Individuals with any lifetime history of psychosis were excluded. Thus the subjects level of clinical symptoms was a
significant factor in determining inclusion and exclusion.
It is of interest that none of the four subjects met criteria
for any other disorder in the schizophrenia spectrum, including schizotypal personality disorder.
It was hypothesized that if schizotaxia in these subjects
was biologically related to schizophrenia, then their
schizotaxic deficits should respond to risperidone, a medication that improves negative symptoms and neuropsychological dysfunction in patients with schizophrenia
(e.g., references 76, 77). Consistent with this prediction, all
four cases (and more recently, a fifth case) showed a reduction in negative symptoms and improvement in tests
of attention after 6 weeks of treatment with risperidone at
a dose range of 0.252.0 mg. These results are preliminary
and require replication in larger, controlled studies before
they can be considered as a basis for treatment. Nevertheless, they imply that in the future, clinical manifestations
of schizotaxia may be amenable to treatment before they
develop further into a psychotic disorder.
If this conceptualization of schizotaxia is correct, this
condition may thus be a more specific expression of the
predisposition to schizophrenia than are the DSM-IV criteria for a diagnosis of schizophrenia. Unlike schizophrenia, schizotaxia is not masked by the florid clinical symptoms and neurotoxic consequences of psychosis that are
also seen in so many other conditions. But before the concept of schizotaxia can be incorporated into the diagnosis
of schizophrenia, its criteria must be validated by demonstrating their predictive and concurrent validity through

1047

REFORMULATING SCHIZOPHRENIA

field trials. Given the nature of schizotaxia, researchers

who are selecting research criteria should consider dimensional as well as categorical criteria. The criteria
would presumably reflect the biological and clinical alterations that occur before the advent of psychosis. This approach would broaden the diagnosis of schizophrenia into
two categoriesschizotaxia and schizotaxia with psychosis (schizophrenia), a categorization analogous to the classification of depression. In this formulation, schizotaxia
with psychosis would be equivalent to the DSM-IV conceptualization of schizophrenia. Schizophrenia without
psychosis would be equivalent to schizotaxia.
Some might argue against this position by claiming that
the distress and disability associated with schizotaxia do
not reach levels that would qualify the condition as a disorder, although many clinical and neurobiologic features
of schizotaxia, such as cognitive deficits in attention, are
well described. Existing research provides little data about
the functional implications of schizotaxia or about
whether treatment is indicated. Investigation of the functional implications of the syndrome is clearly a direction
for future research.
An additional problem is that, given the current state of
knowledge, preventive treatments cannot yet be offered to
people with schizotaxia. Because most cases of schizotaxia would not progress to schizophrenia, treatment
would not be warranted in the absence of evidence for
clinically meaningful impairments. Yet, if efforts at developing preventive interventions are to be taken seriously, it
follows that, someday, diagnostic and therapeutic technologies will reach a point where ethical and effective
treatments of schizotaxia will be possible.
A final problem is that use of the category of schizotaxia
risks dramatically increasing the numbers of people who
are stigmatized with the label of a psychiatric diagnosis.
This possibility may have a variety of implications, some
of which are difficult to predict. A diagnostic label of
schizotaxia may affect both how other people react to
those with the condition and may also affect their view of
themselves. The use of this term could prevent some individuals from getting health insurance coverage, because
they would be deemed high-risk cases. This latter problem
is less worrisome, as it could be solved with the type of legislation that now protects people for whom genetic testing
has revealed a high risk for other illnesses (78). The other
problems underscore the potential importance of genetic
counseling and psychotherapy to help individuals and
families cope with the information that they meet criteria
for schizotaxia. Clearly, there is a need for ethical inquiry
to help balance the ills wrought by stigma with the need to
improve diagnostic nomenclature in a manner that will
someday be relevant for preventive research and intervention (i.e., when schizotaxia genes and genetic and environmental risk factors for psychosis are identified). Moreover, concerns about applying a diagnosis of schizotaxia
(which unlike a diagnosis of schizophrenia, does not de-

1048

note psychosis) will need to be balanced against the potential treatment benefits associated with the identification of people with significant clinical problems.
Whether the term schizotaxia or some other expression
is used, nosologists will need to address both the nonspecificity of psychosis and the existence of a syndrome that
has a biological connection with schizophrenia. The necessity of doing so will become acute after the field develops interventions that will prevent psychosis among people with schizotaxia.
Received June 18, 1999; revision received Nov. 1, 1999; accepted
Nov. 3, 1999. From the Harvard Medical School Department of Psychiatry at the Massachusetts Mental Health Center and Brockton
West Roxbury Veterans Affairs Medical Center; Department of Epidemiology, Harvard School of Public Health, Boston; Pediatric Psychopharmacology Unit, Psychiatry Service, Massachusetts General Hospital, Boston; Harvard Institute of Psychiatric Epidemiology and
Genetics, Boston. Address reprint requests to Dr. Tsuang, Harvard
Medical School Department of Psychiatry at the Massachusetts Mental Health Center, 74 Fenwood Rd., Boston, MA 02115; ming_tsuang
@hms.harvard.edu (e-mail).
Preparation of this chapter was supported in part by NIMH grants
MH-41879, MH-46318, and MH-43518 and a Distinguished Investigator Award from the National Alliance for Research on Schizophrenia
and Depression (Dr. Tsuang) and by the Medical Research, Health Services Research and Development, and Cooperative Studies Programs
of the Department of Veterans Affairs.

References
1. Kendler KS: Toward a scientific psychiatric nosology: strengths
and limitations. Arch Gen Psychiatry 1990; 47:969973
2. Meehl P: Diagnostic taxa as open concepts: metatheoretical
and statistical questions about reliability and construct validity
in the grand strategy of nosological revision, in Contemporary
Directions in Psychopathology: Toward the DSM-IV. Edited by
Millon T, Klerman G. New York, Guilford Press, 1986, pp 215
232
3. Andreasen NC: Understanding schizophrenia: a silent spring?
(editorial). Am J Psychiatry 1998; 155:16571659
4. Kraepelin E: Dementia Praecox and Paraphrenia (1919). Translated by Barclay RM; edited by Robertson GM. New York, Robert E Krieger, 1971
5. Bleuler E: Dementia Praecox or the Group of Schizophrenias
(1911). Translated by Zinkin J. New York, International Universities Press, 1950
6. Blashfield RK: The Classification of Psychopathology: NeoKraepelinian and Quantitative Approaches. New York, Plenum, 1984
7. Klerman GR: Historical background, in Psychiatry, vol 1. Edited
by Michels R, Cooper AM, Guze SB, Judd LL, Klerman GL, Solnit
AJ, Stunkard AJ, Wilner PJ. Philadelphia, JB Lippincott, and New
York, Basic Books, 1988, section 52
8. Robins E, Guze SB: Establishment of diagnostic validity in psychiatric illness: its application to schizophrenia. Am J Psychiatry 1970; 126:983987
9. Schneider K: Clinical Psychopathology. New York, Grune &
Stratton, 1959
10. Schneider K: Klinische Psychopathologie. Stuttgart, Germany,
Georg Thieme Verlag, 1980
11. Frances AJ, First MB, Widiger TA, Miele GM, Tilly SM, Davis WW,
Pincus HA: An A to Z guide to DSM-IV conundrums. J Abnorm
Psychol 1991; 100:407412
12. Millon T: Classification in psychopathology: rationale, alternatives, and standards. J Abnorm Psychol 1991; 100:245261

Am J Psychiatry 157:7, July 2000

TSUANG, STONE, AND FARAONE

13. Gunderson JG, Links PS, Reich JH: Competing models of personality disorders. J Personal Disord 1991; 5:6068
14. Bell RC, Dudgeon P, McGorry PD, Jackson HJ: The dimensionality of schizophrenia concepts in first-episode psychosis. Acta
Psychiatr Scand 1998; 97:334342
15. Crow TJ: From Kraepelin to Kretschmer leavened by Schneider.
Arch Gen Psychiatry 1998; 55:502504
16. Peralta V, Cuesta MJ, Farre C: Factor structure of symptoms in
functional psychoses. Biol Psychiatry 1997; 42:806815
17. Toomey R, Faraone SV, Simpson JC, Tsuang MT: Negative, positive, and disorganized symptom dimensions in schizophrenia,
major depression, and bipolar disorder. J Nerv Ment Dis 1998;
186:470476
18. Gottesman II: Schizophrenia Genesis: The Origin of Madness.
New York, WH Freeman, 1991
19. Tsuang MT, Stone WS, Faraone SV: Schizophrenia: a review of
genetic studies. Harvard Rev Psychiatry 1999; 7:185207
20. Faraone SV, Kremen WS, Lyons MJ, Pepple JR, Seidman LJ,
Tsuang MT: Diagnostic accuracy and linkage analysis: how useful are schizophrenia spectrum phenotypes? Am J Psychiatry
1995; 152:12861290
21. Meehl PE: Schizotaxia, schizotypy, schizophrenia. Am Psychol
1962; 17:827838
22. Meehl PE: Schizotaxia revisited. Arch Gen Psychiatry 1989; 46:
935944
23. Faraone SV, Green AI, Seidman LJ, Tsuang MT: Schizotaxia: clinical implications and new directions for research. Schizophr
Bull (in press)
24. Faraone SV, Seidman LJ, Kremen WS, Pepple JR, Lyons MJ,
Tsuang MT: Neuropsychological functioning among the nonpsychotic relatives of schizophrenic patients: a diagnostic efficiency analysis. J Abnorm Psychol 1995; 104:286304
25. Battaglia M, Torgersen S: Schizotypal disorder: at the crossroads of genetics and nosology. Acta Psychiatr Scand 1996; 94:
303310
26. Battaglia M, Bernardeschi L, Franchini L, Bellodi L, Smeraldi E:
A family study of schizotypal disorder. Schizophr Bull 1995; 21:
3345
27. Crow TJ: The continuum of psychosis and its genetic origins:
the sixty-fifth Maudsley lecture. Br J Psychiatry 1990; 156:788
797
28. Crow TJ: The search for the psychosis gene. Br J Psychiatry
1991; 158:611614
29. Crow TJ: Nuclear schizophrenic symptoms as a window on the
relationship between thought and speech. Br J Psychiatry
1998; 173:303309
30. Collinge J, DeLisi LE, Boccio A, Johnstone EC, Lane A, Larkin C,
Leach M, Lofthouse R, Owen F, Poulter M, Shah T, Walsh C,
Crow TJ: Evidence for a pseudo-autosomal locus for schizophrenia using the method of affected sibling pairs. Br J Psychiatry 1991; 158:624629
31. Parfitt E, Asherson P, Sargeant M, Whatley S, McGuffin P, Owen
M: A linkage study of the pseudoautosomal region in schizophrenia (abstract). Psychiatr Genet 1991; 2:9293
32. DeLisi LE, Devoto M, Lofthouse R, Poulter M, Smith A, Shields G,
Bass N, Chen G, Vita A, Morganti C, Ott J, Crow TJ: Search for
linkage to schizophrenia on the X and Y chromosomes. Am J
Med Genet Neuropsychiatr Genet 1994; 54:113121
33. Peralta V, Cuesta MJ: Diagnostic significance of Schneiders firstrank symptoms in schizophrenia. Br J Psychiatry 1998; 174:
243248
34. Ratakonda S, Gorman JM, Yale SA, Amador XF: Characterization of psychotic symptoms: use of the domains of psychopathology model. Arch Gen Psychiatry 1998; 55:7581
35. Serretti A, Macciardi F, Smeraldi E: Identification of symptomologic patterns common to major psychoses: proposal for a

Am J Psychiatry 157:7, July 2000

36.
37.
38.

39.
40.

41.

42.

43.

44.

45.

46.

47.
48.

49.

50.

51.

52.

phenotype definition. Am J Med Genet Neuropsychiatr Genet

1996; 67:393400
Monti MR, Stanhellini G: Psychopathology: an edgeless razor?
Compr Psychiatry 1996; 37:196204
Kendler KS, Karkowski LM, Walsh D: The structure of psychosis.
Arch Gen Psychiatry 1998; 55:492499
Maziade M, Bissonnette L, Rouillard E, Martinez M, Turgeon M,
Charron L, Pouliot V, Boutin P, Cliche D, Dion C, Fournier JP,
Garneau Y, Lavalee JC, Montgrain N, Nicole L, Pires A, Ponton
AM, Potvin A, Wallot H, Roy MA, Merette C: 6p24-22 region and
major psychoses in the eastern Quebec population. Le Groupe
IREP. Am J Med Genet Neuropsychiatr Genet 1997; 74:311318
Bertelsen A, Gottesman II: Schizoaffective psychoses: genetical
clues to classification. Am J Med Genet 1995; 60:711
Ginns EI, Ott J, Egeland JA, Allen CR, Fann CSJ, Pauls DL, Weissenbach J, Carulli JP, Falls KM, Keith TP, Paul SM: A genomewide search for chromosomal loci linked to bipolar affective
disorder in the Old Order Amish. Nat Genet 1996; 12:431435
Foroud T, Castellucio PF, Koller DL, Edenberg HJ, Goate A, Detera-Wadleigh S, Stine OC, McMahon FJ, McInnis MG, Rice J, Blehar M, Goldin LR, Badner J, Guroff J, Reich T, DePaulo JR, Gershon E, Nurnberger JL: Genomewide scan of affected relative
pairs using the NIMH Genetics Initiative bipolar affective disorder pedigrees. Am J Med Genet 1998; 81:462
Rice JP, Goate A, Williams JT, Bierut L, Dorr D, Wu W, Shears S,
Gopalakrishnan G, Edenberg HJ, Foroud T, Nurnberger J Jr, Gershon ES, Detera-Wadleigh SD, Goldin LR, Guroff JJ, McMahon FJ,
Simpson S, MacKinnon D, McInnis M, Stine OC, DePaulo JR, Blehar MR, Reich T: Initial genome scan of the NIMH Genetics Initiative bipolar pedigrees: chromosomes 1, 6, 8, 10, and 12. Am
J Med Genet Neuropsychiatr Genet 1997; 74:247253
Faraone SV, Matise T, Svrakic D, Pepple J, Malaspina D, Suarez
B, Hampe C, Zambuto CT, Schmitt K, Meyer J, Markel P, Lee H,
Harkevy Friedman J, Kaufmann CA, Cloninger CR, Tsuang MT:
Genome scan of European-American schizophrenia pedigrees:
results of the NIMH Genetics Initiative and Millennium Consortium. Am J Med Genet Neuropsychiatr Genet 1998; 81:290295
Wildenauer D, Hallmaye RJ, Albus M: A susceptibility locus for
affective and schizophrenic disorder? (abstract) Psychiatr
Genet 1996; 6:152
Berrettini WH, Ferraro TN, Goldin LR, Weeks DE, Detera-Wadleigh S, Nurnberger JI Jr, Gershon ES: Chromosome 18 DNA
markers and manic-depressive illness: evidence for a susceptibility gene. Proc Natl Acad Sci USA 1994; 91:59185921
Stine OC, Xu J, Koskela R, McMahon FJ, Gschwend M, Friddle C,
Clark CD, McInnis MG, Simpson SG, Breschel TS, Vishio E, Riskin
K, Feilotter H, Chen E, Chen S, Folstein SE, Meyers DA, Botstein
D, Marr TG, DePaulo JR: Evidence for linkage of bipolar disorder to chromosome 18 with a parent-of-origin effect. Am J
Hum Genet 1995; 57:13841394
Wyatt RJ: Early intervention for schizophrenia: can the course
of the illness be altered? Biol Psychiatry 1995; 38:13
Knoll JL, Garver DL, Ramberg JE, Kingsbury SJ, Croissant D, McDermott B: Heterogeneity of the psychoses: is there a neurodegenerative psychosis? Schizophr Bull 1998; 24:365379
Andreasen NC: A unitary model of schizophrenia: Bleulers
fragmented phrene as schizencephaly. Arch Gen Psychiatry
1999; 56:781787
Seidman LJ: The neuropsychology of schizophrenia: a neurodevelopmental and case study approach. J Neuropsychiatry
1990; 2:301312
Weinberger DR: Schizophrenia as a neurodevelopmental disorder, in Schizophrenia. Edited by Hirsch SR, Weinberger DR. London, Blackwood Press, 1995, pp 293323
Weinberger DR: Neurodevelopmental perspectives on schizophrenia, in Psychopharmacology: The Fourth Generation of

1049

REFORMULATING SCHIZOPHRENIA

53.

54.
55.
56.

57.

58.

59.
60.

61.

62.

63.

64.

65.

66.

Progress. Edited by Bloom FE, Kupfer DJ. New York, Raven

Press, 1995, pp 11711183
Goldman-Rakic PS: More clues on latent schizophrenia point
to developmental origins (editorial). Am J Psychiatry 1995;
152:17011703
Tsuang MT, Faraone SV: Genetic heterogeneity of schizophrenia. Psychiatr Neurol Japn 1995; 97:485501
Bogerts B: Recent advances in the neuropathology of schizophrenia. Schizophr Bull 1993; 19:431445
Shenton ME, Wible CG, McCarley RW: A review of magnetic resonance imaging studies of brain abnormalities in schizophrenia, in Brain Imaging in Clinical Psychiatry. Edited by Krishnan
KRR, Doraiswamy PM. New York, Marcel Dekker, 1997, pp 297
380
Lipska BK, Jaskiw GE, Weinberger DR: Postpubertal emergence
of hyperresponsiveness to stress and to amphetamine after
neonatal excitotoxic hippocampal damage: a potential animal
model of schizophrenia. Neuropsychopharmacology 1993; 9:
6775
Lipska BK, Weinberger DR: Delayed effects of neonatal hippocampal damage on haloperidol-induced catalepsy and apomorphine-induced stereotypic behaviors in the rat. Dev Brain
Res 1993; 75:213222
Seidman LJ: Clinical neuroscience and epidemiology in schizophrenia. Harvard Rev Psychiatry 1997; 3:338342
Faraone SV, Seidman LJ, Kremen WS, Toomey R, Pepple JR,
Tsuang MT: Neuropsychological functioning among the nonpsychotic relatives of schizophrenic patients: a four-year follow-up study. J Abnorm Psychol 1999; 108:176181
Tsuang MT, Gilbertson MW, Faraone SV: Genetic transmission of
negative and positive symptoms in the biological relatives of
schizophrenics, in Negative Versus Positive Schizophrenia. Edited by Marneros A, Andreasen NC, Tsuang MT. New York,
Springer-Verlag, 1991, pp 265291
Kendler KS, Neale MC, Walsh D: Evaluating the spectrum concept of schizophrenia in the Roscommon Family Study. Am J
Psychiatry 1995; 152:749754
Woods BT: Is schizophrenia a progressive neurodevelopmental
disorder? toward a unitary pathogenetic mechanism. Am J Psychiatry 1998; 155:16611670
Nopoulos P, Torres I, Flaum M, Andreasen NC, Ehrhardt JC, Yuh
WTC: Brain morphology in first-episode schizophrenia. Am J
Psychiatry 1995; 152:17211723
Cannon TD, Mednick SA, Parnas J, Schulsinger F, Praestholm J,
Vestergaard A: Developmental brain abnormalities in the offspring of schizophrenic mothers, I: contributions of genetic
and perinatal factors. Arch Gen Psychiatry 1993; 50:551564
Cannon TD, Mednick SA, Parnas J, Schulsinger F, Praestholm J,
Vestergaard A: Developmental brain abnormalities in the offspring of schizophrenic mothers, II: structural brain characteristics of schizophrenia and schizotypal personality disorder.
Arch Gen Psychiatry 1994; 51:955962

1050

67. Arolt V, Lencer R, Achim N, Muller-Myhsok B, Purmann S,

Schurmann M, Leutelt J, Pinnow M, Schwinger E: Eye tracking
dysfunction is a putative phenotypic susceptibility marker of
schizophrenia and maps to a locus on chromosome 6p in families with multiple occurrence of the disease. Am J Med Genet
Neuropsychiatr Genet 1996; 67:560563
68. Freedman R, Coon H, Myles-Worsley M, Orr-Urtreger A, Olincy
A, Davis A, Polmeropoulos M, Holik J, Hopkins J, Hoff M,
Rosenthal J, Waldo MC, Reimherr F, Wender P, Yaw J, Young DA,
Breese C, Adams CR, Patterson D, Adler LE, Kruglyak L, Leonard
S, Byerley W: Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus. Proc Natl Acad Sci USA
1997; 94:587592
69. Catts SV, McConaghy N, Ward PB, Fox AM, Hadzi-Pavlovic D: Allusive thinking in parents of schizophrenics: meta-analysis. J
Nerv Ment Dis 1993; 181:298302
70. Erlenmeyer-Kimling L, Cornblatt B, Friedman D, Marcuse Y,
Rutschmann J, Simmens S, Devi F: Neurological, electrophysiological, and attentional deviations in children at risk for schizophrenia, in Schizophrenia as a Brain Disease. Edited by Henn
FA, Nasrallah HA. New York, Oxford University Press, 1982, pp
6198
71. Friedman D, Squires-Wheeler E: Event-related potentials (ERPs)
as indicators of risk for schizophrenia. Schizophr Bull 1994; 20:
6374
72. Seidman LJ, Faraone SV, Goldstein JM, Goodman JM, Kremen
WS, Toomey R, Tourville J, Kennedy D, Makris N, Caviness VS,
Tsuang MT: Thalamic and amygdala-hippocampal volume reductions in first degree relatives of patients with schizophrenia: an MRI-based morphometric analysis. Biol Psychiatry
1999; 46:941954
73. Kremen WS, Seidman LJ, Pepple JR, Lyons MJ, Tsuang MT, Faraone SV: Neuropsychological risk indicators for schizophrenia: a
review of family studies. Schizophr Bull 1994; 20:103119
74. Tsuang MT, Stone WS, Seidman LJ, Faraone SV, Zimmet S,
Wojcik J, Kelleher J, Green AI: Treatment of nonpsychotic relatives of patients with schizophrenia: four case studies. Biol Psychiatry 1999; 41:14121418
75. Andreasen NC: Scale for the Assessment of Negative Symptoms
(SANS). Iowa City, University of Iowa, 1983
76. Rossi A, Mancini F, Stratta P, Mattei P, Gismondi R, Pozzi F,
Casacchia M: Risperidone, negative symptoms and cognitive
deficit in schizophrenia: an open study. Acta Psychiatr Scand
1997; 95:4043
77. Green MF, Marshall BD Jr, Wirshing WC, Ames D, Marder SR,
McGurk S, Kern RS, Mintz J: Does risperidone improve verbal
working memory in treatment-resistant schizophrenia? Am J
Psychiatry 1997; 154:799804
78. Faraone SV, Tsuang D, Tsuang MT: Psychiatric Genetics: A Guide
for Mental Health Professionals. New York, Guilford, 1999

Am J Psychiatry 157:7, July 2000